Novartis drug Afinitor® approved by FDA as first medication to treat patients with non-cancerous kidney tumors associated with TSC

Thursday, 26. April 2012 23:50

Novartis International AG /Novartis drug Afinitor® approved by FDA as first medication to treat patients with non-cancerous kidney tumors associated with TSC . Processed and transmitted by Thomson Reuters ONE.The issuer is solely responsible for the content of this announcement.

* Kidney tumors affect up to 80% of patients with tuberous sclerosis complex (TSC) and growing tumors may lead to unpredictable life-threatening complications[1] * Prior to the approval of Afinitor, surgical intervention was the only treatment option for patients with these kidney tumors associated with TSC[2],[3] * Approval marks the second TSC-related indication for Afinitor in the US, where it is also approved to treat subependymal giant cell astrocytoma (SEGA) in TSC[3]

Basel, April 26, 2012 - Novartis announced today that the US Food and DrugAdministration (FDA) approved Afinitor(®) (everolimus) tablets* for thetreatment of adult patients with kidney tumors known as renal angiomyolipomasand tuberous sclerosis complex (TSC), who do not require immediate surgery[2].This marks the first approval of a medical treatment in this patientpopulation[2],[3].

The accelerated approval was based on the Phase III EXIST-2 (EXaminingeverolimus In a Study of TSC) trial, which found that 42% of patients oneverolimus experienced an angiomyolipoma response versus 0% of patients in theplacebo arm (p<0.0001)[2],[4]. The time to angiomyolipoma progression was alsostatistically significantly longer in patients on everolimus (p<0.0001). Amongthe 97% of trial patients with skin lesions, one of the key concerns for themajority of patients with TSC, a 26% response rate was seen with everolimusversus 0% with placebo (p=0.0011)[2],[5].

"Renal angiomyolipomas are one of the greatest causes of morbidity and mortalityin adult TSC patients and can be one of the most challenging aspects of thedisease to treat," said John Bissler, MD, Clark D. West Endowed Chair ofNephrology at Cincinnati Children's Hospital Medical Center. "Today marks animportant step for the TSC community, as Afinitor is now the only approvedmedicine to reduce the kidney tumor burden in these patients."

Up to 80% of patients with TSC, a genetic disorder that may cause non-canceroustumors to form in vital organs, will develop renal angiomyolipomas. Typicalonset occurs between the ages of 15 and 30 and prevalence increases with age.Over time, these tumors may grow large enough to cause severe internal bleeding,require emergency surgical interventions, such as embolization and nephrectomy,or lead to kidney failure[1]. The tumors can be difficult to manage as theyoften form in both kidneys[5],[6]. In addition, skin lesions occur in more than90% of patients with TSC[7]. They may develop in infancy, can become moreprevalent with age and cause disfigurement[1],[5].

"With this FDA approval, Afinitor becomes the first medical option to treat twoof the most debilitating manifestations of this challenging, lifelong disease -kidney tumors called renal angiomyolipomas and brain tumors known as SEGAs,"said Hervé Hoppenot, President, Novartis Oncology. "This approval furtherstrengthens our commitment to address unmet needs in TSC as we continue toresearch everolimus and mTOR inhibition across other manifestations of thedisease."

Based on an effect on a clinical endpoint other than survival or irreversiblemorbidity, this indication was approved under the FDA's accelerated approvalprogram, which provides patients access to a treatment for a serious or life-threatening illness and that provides meaningful therapeutic benefit to patientsover existing treatments[2]. Novartis previously received approval foreverolimus for the treatment of adult and pediatric patients, aged three orolder, with subependymal giant cell astrocytoma (SEGA) associated with TSC whorequire therapeutic intervention but are not candidates for curative surgicalresection in the US, and in more than 40 additional countries. Filings for renalangiomyolipoma are under way in multiple countries outside of the US.

Afinitor works by inhibiting mTOR, a protein implicated in many tumor-causingpathways[1],[8]. TSC is caused by defects in the TSC1 and/or TSC2 genes[1]. Whenthese genes are defective, mTOR activity is increased, which can causeuncontrolled tumor cell growth and proliferation, blood vessel growth andaltered cellular metabolism[8],[9]. According to preclinical studies, byinhibiting mTOR activity in this signaling pathway, everolimus reduces cellproliferation and blood vessel growth[1],[2].

Affecting approximately one to two million people worldwide, TSC can affect manydifferent parts of the body, including the kidneys and brain, as well as theheart, lungs and skin. Tuberous sclerosis complex is associated with a varietyof resulting disorders, including skin lesions, seizures, swelling in the brain(hydrocephalus), kidney failure, developmental delays and behavioral issues[1].

About EXIST-2EXIST-2 is the first double-blind, randomized, placebo-controlled,international, multicenter Phase III study for the treatment of patients withrenal angiomyolipoma associated with TSC[2],[4]. Trial patients (median age=31,range 18-61) were randomized 2:1 to receive either everolimus (n=79) or placebo(n=39) at a daily starting dose of 10 mg. By the cut-off of October 14, 2011,the median treatment duration in the double-blind period was 48 weeks in theeverolimus arm and 45 weeks in the placebo arm[2].

In the study, 42% of patients on everolimus (33 of 79; 95% CI 30.8-53.4)experienced an angiomyolipoma response versus 0% on placebo (0 of 39; 95% CI0.0-9.0)(p<0.0001), defined as a 50% or greater reduction in the sum ofangiomyolipoma volume relative to baseline, the absence of new tumor growth atleast 1 cm in longest diameter, absence of kidney volume increase of 20% orgreater and no renal angiomyolipoma-related bleeding of Grade 2 or higher[2].

Everolimus demonstrated superiority to placebo for both supportive efficacyoutcomes measured: time to angiomyolipoma progression and skin lesion responserate. There were three patients in the Afinitor arm and eight patients in theplacebo arm with documented angiomyolipoma progression by central radiologicreview. The time to angiomyolipoma progression was statistically significantlylonger in patients on everolimus (p<0.0001; HR 0.08, 95% CI 0.02-0.37). Skinlesion response rate was significantly higher in the everolimus arm. A partialclinical response in skin lesions (corresponding to a 50% or greaterimprovement) was observed by Physician Global Assessment in 26% of patients oneverolimus, compared with 0% of patients on placebo (p=0.0011). No completeresponses were observed[2].

The most common adverse event (AE) in the everolimus arm (with an incidence ofat least 30%) was stomatitis. The most common Grade 3-4 adverse reactions(incidence >= 2%) were stomatitis, amenorrhea and convulsion. The most commonlaboratory abnormalities (incidence >= 50%) were hypercholesterolemia,hypertriglyceridemia and anemia. The most common Grade 3-4 laboratoryabnormality (incidence >= 3%) was hypophosphatemia. Adverse events observed inthis study were for the most part consistent with the known safety profile ofeverolimus in the TSC setting[2].

About everolimusEverolimus is now approved as Afinitor(®) (everolimus) tablets in the UnitedStates (US) for the treatment of adult patients with renal angiomyolipomas andtuberous sclerosis complex (TSC), who do not require immediate surgery. Theeffectiveness of Afinitor in treatment of renal angiomyolipoma is based on ananalysis of durable objective responses in patients treated for a median of 8.3months. Further follow-up of patients is required to determine long-termoutcomes. Everolimus is also approved in the European Union (EU) as Votubia(®)(everolimus) tablets and in the US as Afinitorto treat adult and pediatricpatients, aged three years or older, with SEGA associated with TSC who requiretherapeutic intervention but are not candidates or amenable for surgery. Theeffectiveness of everolimus is based on an analysis of change in SEGA volume inpatients three years of age and older. Further clinical benefit has not beendemonstrated.

Everolimus is approved as Afinitor in more than 80 countries including the USand throughout the EU in the adult oncology settings of advanced renal cellcarcinoma following progression on or after vascular endothelial growth factor(VEGF)-targeted therapy in the EU and after failure of treatment with sunitinibor sorafenib in the US. Afinitor is approved for the treatment of locallyadvanced, metastatic or unresectable progressive neuroendocrine tumors ofpancreatic origin in adults in the US and EU.

Everolimus is also available from Novartis for use in other non-oncology patientpopulations under the brand names Certican(®) and Zortress(®) and is exclusivelylicensed to Abbott and sublicensed to Boston Scientific for use in drug-elutingstents.

Indications vary by country and not all indications are available in everycountry.

Important safety information about Afinitor/VotubiaAfinitor/Votubia can cause serious side effects including lung or breathingproblems, infections, and renal failure which can lead to death. Mouth ulcersand mouth sores are common side effects. Afinitor/Votubia can affect blood cellcounts, kidney and liver function, and blood sugar and cholesterol levels.Afinitor/Votubia may cause fetal harm in pregnant women. Women takingAfinitor/Votubia should not breast feed.

DisclaimerThe foregoing release contains forward-looking statements that can be identifiedby terminology such as "commitment," "continue to," "under way," or similarexpressions, or by express or implied discussions regarding potential newindications or labeling for Afinitor or regarding potential future revenues fromAfinitor. You should not place undue reliance on these statements. Such forward-looking statements reflect the current views of management regarding futureevents, and involve known and unknown risks, uncertainties and other factorsthat may cause actual results with Afinitor to be materially different from anyfuture results, performance or achievements expressed or implied by suchstatements. There can be no guarantee that Afinitor will be approved for any newindications or labeling in any market, or at any particular time. Nor can therebe any guarantee that Afinitor will achieve any particular levels of revenue inthe future. In particular, management's expectations regarding Afinitor could beaffected by, among other things, unexpected regulatory actions or delays orgovernment regulation generally; unexpected clinical trial results, includingunexpected new clinical data and unexpected additional analysis of existingclinical data; competition in general; government, industry and general publicpricing pressures; unexpected manufacturing issues; the company's ability toobtain or maintain patent or other proprietary intellectual property protection;the impact that the foregoing factors could have on the values attributed to theNovartis Group's assets and liabilities as recorded in the Group's consolidatedbalance sheet, and other risks and factors referred to in Novartis AG's currentForm 20-F on file with the US Securities and Exchange Commission. Should one ormore of these risks or uncertainties materialize, or should underlyingassumptions prove incorrect, actual results may vary materially from thoseanticipated, believed, estimated or expected. Novartis is providing theinformation in this press release as of this date and does not undertake anyobligation to update any forward-looking statements contained in this pressrelease as a result of new information, future events or otherwise.

About NovartisNovartis provides innovative healthcare solutions that address the evolvingneeds of patients and societies. Headquartered in Basel, Switzerland, Novartisoffers a diversified portfolio to best meet these needs: innovative medicines,eye care, cost-saving generic pharmaceuticals, preventive vaccines anddiagnostic tools, over-the-counter and animal health products. Novartis is theonly global company with leading positions in these areas. In 2011, the Group'scontinuing operations achieved net sales of USD 58.6 billion, whileapproximately USD 9.6 billion (USD 9.2 billion excluding impairment andamortization charges) was invested in R&D throughout the Group. Novartis Groupcompanies employ approximately 124,000 full-time-equivalent associates andoperate in more than 140 countries around the world. For more information,please visit http://www.novartis.com.

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*Known as Votubia® (everolimus) tablets for certain patients with SEGAassociated with TSC in the EU and Switzerland.

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